Rabbit anti-human thymocyte immunoglobulin 25 mg per vial. 1 ml reconstituted solution contains 5 mg rabbit, anti-human thymocyte immunoglobulin.

Powder for solution for infusion

- Immunosuppression in solid organ transplantation - Prevention of graft rejection in renal transplantation - Treatment of steroid resistant graft rejection in renal transplantation - Prevention of graft rejection in heart transplantation. -Thymoglobuline is usually used in combination with other immunosuppressive drugs

Thymoglobuline must always be used under strict medical supervision and prescribed by physicians with experience in using immunosuppressive agents.

Posology

The posology depends on the indication, the administration regimen and the combination with other immunosuppressive agents.

The following dosage may be used as a reference. Treatment can be discontinued without gradual tapering of the dose.

Immunosuppression in solid organ transplantation

Prophylaxis of graft rejection

1 to 1.5 mg/kg/day for 3 to 9 days after transplantation of a kidney, corresponding to a cumulative dose of 3 to 13.5 mg/kg.

1 to 2.5 mg/kg/day for 3 to 5 days after transplantation of a heart, corresponding to a cumulative dose of 3 to 12.5 mg/kg.

Treatment of steroid resistant graft rejection:

1.5 mg/kg/day for 7 to 14 days after transplantation of a kidney, corresponding to a cumulative dose of 10.5 to 21 mg/kg.

Dose modifications

For obese patients dosing should be based on ideal weight rather than actual weight.

Paediatric and elderly patients

The dosage recommendations in the paediatric population (infants, children and adolescents) and elderly patients are the same as for adults. There are no paediatric data for the treatment of graft rejection in renal transplantation.

Renal and hepatic impairment

In view of the PK and metabolism no dose adjustment is necessary in patients with hepatic and/or renal impairment.

Method of administration

Thymoglobuline is usually administered in the context of a therapeutic regimen combining multiple immunosuppressive agents.

It is recommended to administer pre-medication with intravenous corticosteroids and antihistamines prior to infusion of rabbit anti-human thymocyte globulin. Anti-pyretic agents (e.g. paracetamol) may also increase the tolerability of the initial infusion.

Rabbit anti-human thymocyte globulin is infused after dilution in isotonic 0.9 % sodium chloride or 5 % glucose solution. Inspect solution for particulate matter after reconstitution. To avoid inadvertent administration of particulate matter from reconstitution, it is recommended that Thymoglobuline is administered through a 0.22 μm in-line filter.

Infuse slowly into a high-flow vein. Adjust the infusion rate so that the total duration of infusion is not less than 6 hours.

Thymoglobuline is contraindicated in patients with:

• Hypersensitivity to rabbit proteins or to any product excipients.

• Active acute or chronic infections, which would contraindicate any additional immunosuppression.

Thymoglobuline should be used under strict medical supervision in a hospital setting. Thymoglobuline must only be administered according to the instructions of a physician with experience of immunosuppressive therapy in the transplant setting. Patients should be carefully monitored during the infusion. Particular attention must be paid to monitoring the patient for any symptoms of anaphylactic shock. Close monitoring of the patient must continue during the infusion and for a period of time following the end of the infusion until the patient is stable.

Prior to administration of Thymoglobuline it is advisable to determine whether the patient is allergic to rabbit proteins. Medical personnel and equipment, etc. must be readily at hand during the first days of therapy to provide emergency treatment if necessary.

Warnings

Immune-mediated reactions

In rare instances, serious immune-mediated reactions have been reported with the use of Thymoglobuline and consist of anaphylaxis or severe cytokine release syndrome (CRS).

Very rarely, fatal anaphylaxis has been reported. If an anaphylactic reaction occurs, the infusion should be terminated immediately and appropriate emergency treatment should be initiated. Equipment for emergency therapy for anaphylactic shock must be readily available.

Any further administration of Thymoglobuline to a patient who has a history of anaphylaxis to Thymoglobuline should only be undertaken after serious consideration.

Severe, acute infusion-associated reactions (IARs) are consistent with CRS which is attributed to the release of cytokines by activated monocytes and lymphocytes. In rare instances, these reported reactions are associated with serious cardiorespiratory events and/or death.

Infection

Thymoglobuline is routinely used in combination with other immunosuppressive agents. Infections (bacterial, fungal, viral and protozoal), reactivation of infection (particularly CMV) and sepsis have been reported after Thymoglobuline administration in combination with multiple immunosuppressive agents. In rare cases, these infections have been fatal.

Precautions

General

Appropriate dosing for Thymoglobuline is different from dosing for other anti-thymocyte globulin (ATG) products, as protein composition and concentrations vary depending on the source of ATG used. Physicians should therefore exercise care to ensure that the dose prescribed is appropriate for the ATG product being administered.

Thymoglobuline should be used under strict medical supervision in a hospital setting. Patients should be carefully monitored during the infusion and for a period of time following the end of the infusion until the patient is stable. Close compliance with the recommended dosage and infusion time may reduce the incidence and severity of IARs. Additionally, reducing the infusion rate may minimize many of these adverse reactions. Premedication with antipyretics, corticosteroids, and/or antihistamines may decrease both the incidence and severity of these adverse reactions.

Rapid infusion rates have been associated with case reports consistent with cytokine release syndrome (CRS). In rare instances, severe CRS can be fatal.

Haematological Effects

Thrombocytopenia and/or leukopenia (including lymphopenia and neutropenia) have been identified and are reversible following dose adjustments. When thrombocytopenia and/or leukopenia are not part of the underlying disease or associated with the condition for which Thymoglobuline is being administered, the following dose reductions are suggested:

• A reduction in dosage must be considered if the platelet count is between 50,000 and 75,000 cells/mm³ or if the white cell count is between 2,000 and 3,000 cells/mm³;

• Stopping Thymoglobuline treatment should be considered if persistent and severe thrombocytopenia (<50,000 cells/mm³) occurs or leukopenia (<2,000 cells/mm³) develops.

White blood cell and platelet counts should be monitored during and after Thymoglobuline therapy. Patients with severe neutropenic aplastic anaemia require very careful monitoring, appropriate prophylaxis and treatment of fevers and infections as well as adequate platelet transfusion support.

Infection

Infections, reactivation of infection (particularly CMV) , and sepsis have been reported after Thymoglobuline administration in combination with multiple immunosuppressive agents. Careful patient monitoring and appropriate anti-infective prophylaxis are recommended.

Malignancy

Use of immunosuppressive agents, including Thymoglobuline, may increase the incidence of malignancies, lymphoma or post-transplant lymphoproliferative disease (PTLD).

Risk of Transmission of Infectious Agents

Human blood components (formaldehyde treated red blood cells), as well as thymus cells are used in the manufacturing process for Thymoglobuline. Standard measures to prevent infections resulting from the use of medicinal products prepared using human components include selection of donors, screening of individual donations for specific markers of infection and the inclusion of effective manufacturing steps for inactivation/removal of viruses.

Despite this, when medicinal products prepared using human components are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken for Thymoglobuline are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses such as HAV and parvovirus B19.

It is strongly recommended that every time that Thymoglobuline is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Special Considerations for Thymoglobuline Infusion

As with any infusion, reactions at the injection site can occur and may include pain, swelling, and erythema.

The recommended route of administration for Thymoglobulin is intravenous infusion using a high-flow vein; however, it may be administered through a peripheral vein. When Thymoglobuline is administered through a peripheral vein, concomitant use of heparin and hydrocortisone in an infusion solution of 0.9% sodium chloride may minimize the potential for superficial thrombophlebitis and deep vein thrombosis.

The combination of Thymoglobuline, heparin and hydrocortisone in a dextrose infusion solution has been noted to precipitate and is not recommended.

Immunisations

The safety of immunisation with attenuated live vaccines following Thymoglobuline therapy has not been studied; therefore, immunisation with attenuated live vaccines is not recommended for patients who have recently received Thymoglobuline.

No drug interaction studies have been performed.

Interactions with food and drink are unlikely.

Thymoglobuline has not been shown to interfere with any routine clinical laboratory tests which use immunoglobulins. However, Thymoglobuline can induce production of human anti-rabbit antibodies which may interfere with rabbit antibody-based immunoassays and with cross-match or panel-reactive antibody cytotoxicity assays. Thymoglobuline may interfere with ELISA tests.

Genzyme Therapeutics

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